p53 and p73 in suppression of Myc-driven lymphomagenesis.
Induction of apoptosis by the tumor suppressor p53 is known to protect from Myc-driven lymphomagenesis. The p53 family member p73 is also a proapoptotic protein, which is activated in response to oncogenes like Myc. Here, we have investigated whether p73 provides a similar protection from Myc-driven lymphomas as p53. Confirming previous studies, the inactivation of a single p53 allele (p53+/-) strongly reduced the median survival of Emu-Myc transgenic mice from 103 to 39 days and was invariably associated with a loss of the wild-type p53 allele. In contrast, mutational inactivation of a p73 allele (p73+/-) reduced the median survival by only 12 days. Lymphomas that developed in the p73+/- background showed no loss of heterozygosity (LOH). Furthermore, gene expression profiling of p73+/+, p73+/- and p73-/- lymphomas indicated that p73+/- lymphomas retained p73 transcriptional activity. Subtle gene expression differences between p73+/+ and p73+/- lymphomas, however, suggest a haploinsufficient phenotype on some p73 target genes. This might help to explain why p73+/- animals succumbed to disease slightly earlier than their p73+/+ littermates (log-rank test p<0.0395) and why p73 often shows monoallelic inactivation in human lymphomas. Together these data demonstrate that in Myc-driven lymphomagenesis p73 has weak tumor suppressor activity compared with p53.
Griesmann
Heidi
H
Department for Hematology, Oncology and Immunology, Philipps-University Marburg, Marburg, Germany.
Schlereth
Katharina
K
Krause
Michael
M
Samans
Birgit
B
Stiewe
Thorsten
T
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins